This HIV Prevention Trials Network (HPTN) Coordinating and Operations Center (CORE) application is submitted by Family Health International with applications from two affiliated organizations, John Hopkins University as the Central Laboratory (CL) and the Fred Hutchinson Cancer Research Center as the Statistical and Data Management Center (SDMC). The CORE application describes a coordinated research agenda designed to evaluate the safety and efficacy of emerging interventions to prevent sexual, perinatal, and parenteral transmission of HIV using HIV incidence as primary trial endpoint. To address these routes of transmission, six key scientific areas with unique research priorities have been delineated-perinatal transmission, microbicides, sexual behavior, STD control, antiretroviral therapies, and injection drug use. The special opportunities offered by this HPTN application involve: 1) its leadership by experts in the prevention sciences to set research priorities amidst a rapidly evolving HIV scientific arena; 2) its coordinated domestic-international research agenda; 3) its multi- disciplinary study teams of behavioral, clinical, epidemiologic, and statistical scientists; 4) its streamlined process for moving from study concept to study operation; and 5) its ability to conduct cross-cultural comparisons. The HPTN has be designed to allow for: 1) rapid consideration of hypothesis-driven concept plans by six science working groups, 2) prioritization and approval of a coordinated research agenda at the Executive Committee level, 3) implementation by pluripotential HPTN sites, and 4) careful oversight and rigorous evaluation by the Prevention Leadership Group. Close linkages available through the leadership in HPTN will assure that emerging knowledge about effective HIV prevention interventions is scaled up through domestic prevention agencies (CDC) and international donors (USAID, World Bank; UNAIDS). The HPTN and CORE organizational structure and operation, and a transition plan for moving HIVNET operations into the HPTN strategic plan are also described in this application. In summary, over the next five years, this HTPN application is proposing an aggressive, state-of-the-art prevention science research agenda designed to advance knowledge in the complex arena of reducing HIV transmission. This research agenda will be implemented under the direction of Willard Cates, Jr., MD, MPH and a leadership team comprised of world class scientists and supported by the CORE at Family Health International.